EP0062440A1 - Process for preparing phenylalkanoic acids and derivatives of benzoxazole therefrom - Google Patents

Process for preparing phenylalkanoic acids and derivatives of benzoxazole therefrom Download PDF

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Publication number
EP0062440A1
EP0062440A1 EP82301482A EP82301482A EP0062440A1 EP 0062440 A1 EP0062440 A1 EP 0062440A1 EP 82301482 A EP82301482 A EP 82301482A EP 82301482 A EP82301482 A EP 82301482A EP 0062440 A1 EP0062440 A1 EP 0062440A1
Authority
EP
European Patent Office
Prior art keywords
acid
mixture
hydrogen
formula
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP82301482A
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German (de)
English (en)
French (fr)
Inventor
James Michael Greene
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0062440A1 publication Critical patent/EP0062440A1/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles

Definitions

  • This invention belongs to the field of synthetic organic chemistry, and provides a particularly advantageous process for preparing certain phenyl- alkanoic acids from the corresponding benzaldehydes or phenyl ketones.
  • the process provides the desired acids in high yield and acceptable purity without isolation of intermediate products.
  • This invention provides a process for preparing an acid of the formula (I) wherein R is hydrogen or C 1 -C 3 alkyl; one of R 1 and R 2 is hydrogen and the other is hydroxy; provided that R is hydrogen or methyl when R 2 is hydroxy; comprising catalytically hydrogenating a compound of the formula in the presence of an amine of the formula wherein R 3 is C l -C 3 alkyl and R 4 is hydrogen or C l -C 3 alkyl, in an inert organic solvent to prepare a compound of the formula adding an alkali metal cyanide to the mixture; holding the mixture at from about 100° to about 150° until a compound of the formula is formed; removing the solvent; adding aqueous alkali metal hydroxide; holding the mixture at from about 75° to about 125° until the product is formed; and making the mixture acid.
  • the separation of the product acid is preferably accomplished by heating the acidified reaction mixture containing the acid of formula (I) to about 75°-125°; filtering it at about 75°-125°; cooling the mixture; extracting the mixture with an inert organic solvent; and isolating the acid from the organic solvent.
  • C 1 -C 3 alkyl refers to the groups methyl, ethyl, propyl and isopropyl.
  • a preferred group of products of this invention includes the compounds wherein R is hydroxy.
  • Another preferred group of compounds includes those wherein R is hydrogen, another preferred group includes those wherein R is methyl, and a particularly preferred compound is 4-hydroxy- ⁇ -methylphenylacetic acid.
  • the concentration of the reaction mixtures is not critical. In the various steps below, an indication of the desired concentration range is given, but it is not implied that the concentrations suggested are limitations in any way on the operability of the process.
  • the starting compound which is a hydroxybenzaldehyde when the group R is hydrogen, or is a phenyl alkyl ketone when R is an alkyl group
  • the starting compound is hydrogenated catalytically in the presence of a suitable alkylamine to form the corresponding amino compound.
  • the amine may be either a monoalkylamine, or a dialkylamine. It is preferred to use a dialkylamine when the starting compound is a hydroxybenzaldehyde, and to use a monoalkylamine when the starting compound is a ketone.
  • Suitable monoalkylamines include, for example, methylamine, ethylamine and propylamine; dialkylamines include ethylmethyla - mine, dimethylamine, diethylamine, dipropylamine and ethylpropylamine.
  • the preferred monoalkylamine is methylamine, and the preferred dialkylamine is dimethylamine.
  • the preferred solvent for the reductive amination step is dimethylformamide. It is preferred because of its high boiling point and stability, which properties make it particularly advantageous both in the amination step and in the following cyanation step. Other solvents, however, may be used in particular circumstances, particularly dimethylacetamide, hexamethylphosphoramide and dimethylsulfoxide.
  • the usual hydrogenation catalysts are used in the reductive amination.
  • the preferred catalyst is carbon-supported palladium, but other catalysts, such as platinum, platinum oxide, nickel, rhodium and ruthenium may be used as desired.
  • Hydrogen pressures from about 2 atmospheres to about 150 atmospheres are used, as is usual in the art, and the preferred process temperature is the ambient temperature. Temperatures as high even as about 100° may be used, however.
  • a convenient concentration for the step is in the range of 1-2 gram-moles per liter, but higher and lower concentrations are readily used as may be dictated by operating convenience in a given situation.
  • the reaction mixture is removed from the hydrogenator.
  • the catalyst may be separated from it, usually by filtering or centrifuging the mixture, or may be left in the mixture to be filtered out later.
  • alkali metal cyanide is added to the reaction mixture from the first step.
  • the preferred cyanide is sodium cyanide, but other alkali metal cyanides such as potassium or lithium cyanide may be used as well if desired.
  • the mixture is then heated to an elevated temperature in the range of from about 100° to about 150°, and is stirred at that temperature until the desired acetonitrile is formed.
  • the preferred temperature is in the range of from about 120° to about 150°, and the optimum reaction time, when a temperature in that range is used, is about 4 to 8 hours.
  • the solvent is distilled from the reaction mixture, as by putting the mixture under vacuum while the vessel is heated. It is not necessary to continue the distillation until the mixture is analytically free of solvent; the later hydrolysis step will hydrolyze and remove the remaining solvent, especially when the solvent is dimethylformamide, so that residual solvent does not interfere with the isolation of the final product.
  • the product from the cyanation step, after the solvent has been distilled, is a thick oily or greasy residue.
  • the phenylacetonitrile compound is converted to the desired carboxylic acid by a basic hydrolysis in the presence of an aqueous solution of an alkali metal hydroxide.
  • the preferred base is sodium hydroxide, but potassium and lithium hydroxides also may be used advantageously.
  • the reaction mixture is most easily prepared by simply adding the aqueous base to the residue remaining after the distillation of solvent from the cyanation step reaction mixture.
  • the concentration of the aqueous solution of base is not critical. Relatively high concentrations, from about 10% to about 40%, are satisfactory and are preferred because of the economy and convenience of such operation. Lower concentrations can be used but are not preferred.
  • the basic mixture is heated to a temperature from about 75° to about 125° to accomplish the hydrolysis. Operation under pressure is of course necessary if a temperature above the boiling point is to be used. It is preferred to operate at the reflux temperature of the mixture, about 100°. Reaction times in the range of about 4 to 8 hours have been found to give essentially complete hydrolysis at the reflux temperature; operation at higher temperatures will, of course, allow shorter periods of time in the hydrolysis step.
  • the reaction mixture is worked up.
  • the first step in the preferred workup procedure is to make the mixture acid, preferably with an inexpensive mineral acid such as hydrochloric acid.
  • Other acids may of course be used, so long as the neutralization product of the acid and the base used in the hydrolysis step is a water-soluble salt. Accordingly, sulfuric acid, phosphoric acid and the like may be used as may be convenient in the circumstances.
  • the mixture is preferably acidified to a pH of about 2.
  • Activated charcoal has been found to be effective for the purpose, and a particularly advantageous point to apply it is at the end of the hydrolysis step, while the product is still in the water solution.
  • the decolorizing agent is conveniently added either before or after the reaction mixture is made acid, and is filtered out in the filtration step which follows.
  • the acid mixture is then heated to a temperature in the range of from about 75° to about 125° (operation under pressure is necessary to achieve temperatures above 100°, of course) and is held at that temperature with stirring for a brief period of time in the range of from a few minutes to an hour.
  • the mixture is then filtered in equipment which allows it to be held at a temperature in the range of about 75-125° while it is filtered.
  • Ordinary filter paper with a filter aid pad gives adequate separation of the insoluble impurities, with acceptable speed of filtration.
  • the filtrate is then cooled to a temperature which approximates ambient temperature, and is extracted with an inert organic solvent.
  • the preferred solvents are esters, especially ethyl acetate.
  • Other solvents can be used as well, such as ethers, including tetrahydrofuran and diethyl ether, for example.
  • the extracting solvent must be water-immiscible, and must have adequate solvency for the phenylacetic acid.
  • the amount of solvent should be in the range of from about 500 ml. per gram-mole of starting compound to about 2.5 liters per gram-mole of starting compound.
  • the exact amount of solvent is not critical, but can be adjusted as may be convenient in a given instance, and in accordance with the relative value of extremely complete extraction of the product, as compared with the cost of solvent. It is advantageous, of course, to extract the mixture 2 or more times, adding the solvent in portions.
  • the product phenylacetic acid is isolated from the organic solvent.
  • the isolation may be carried out by simply evaporating the solvent, leaving the product as the residue. To do so is difficult in large scale operation, however, and any of a number of expedients may be used.
  • the solvent can be evaporated, and the product can then be taken up as a suspension in a non-solvent such as hexane and recovered by filtration or centrifugation.
  • the residual product can be dissolved in a relatively weak solvent for it, such as, for example, warm toluene or xylene.
  • the process of this invention will easily produce the phenylacetic acids in overall yields of 85-95%, and in excellent purity.
  • U.S. Reissue Patent 29,608 shows a group of benzoxazoles which are analgesics and antiinflammatories, and which have a carboxylic acid group, such as that of the 4-hydroxy acids produced by this invention, at the 5-or 6-position of their phenyl ring.
  • the acids are converted to those benzoxazoles by the following steps:
  • R is a para-chloro substituent and R 4 is hydrogen, since the product of the reaction is then benoxaprofen.
  • the 4-hydroxy product of the process of this invention wherein R is hydrogen can also be used as an intermediate in preparing certain ⁇ -lactam antibiotics, particularly those taught in U.S. Patents 4,138,486 and 4,201,782, both of Shionogi and Co.
  • the compounds of those patents are oxa- ⁇ -lactam compounds, having a carboxy(4-hydroxyphenyl)acetamido side chain.
  • the 4-hydroxyphenylacetic acid prepared by this invention is a useful starting compound to prepare the side chain group, as explained by Greene and Bunnell in U.S. Patent Application 203,736.
  • the process of this example was carried out substantially according to the process of Example 1, except that, after the hydrolysis reaction mixture had been made acid with hydrochloric acid, and then heated to reflux, 3 g. of activated carbon was added and it was stirred under reflux for 30 minutes. The mixture was then filtered through a filter aid pad, using a steam- jacketed Buchner funnel, and the filtrate was cooled and extracted twice with 125 ml. portions of ethyl acetate. The ethyl acetate layers were combined and evaporated, and the product was recovered and dried as described in Example 1 to obtain 28.3 g. of the desired product, equivalent to 85% of the theoretical yield of the process. The product was identical to that of Example 1.
  • a 24.4 g. portion of 4-hydroxybenzaldehyde was dissolved in 100 ml. of dimethylformamide, and the solution was cooled in an ice bath. To it was added 18 g. of anhydrous dimethylamine, and 0.1 g. of platinum oxide hydrogenation catalyst. The mixture was put under 50 psig of hydrogen in an agitated hydrogenator for 1 hour and 15 minutes, during which time it took up 16 psi of hydrogen, the theoretical uptake. The mixture was then filtered into another container, and the hydrogenator and filter were washed with 20 ml. of additional dimethylformamide. To the filtrate was added 10.8 g. of sodium cyanide, and the mixture was stirred at 130° for 6 hours.
  • the solvent was then removed under vacuum at 80° to obtain 49.6 g. of a dark residue.
  • 150 ml. of water and 20 g. of sodium hydroxide pellets were added, and the aqueous mixture was stirred under reflux for 6 hours. It was then cooled to ambient temperature, and its pH was adjusted to 1.8 by the addition of about 60 ml. of concentrated hydrochloric acid.
  • Six g. of activated carbon was added, and the mixture was heated briefly to reflux. It was then filtered at the boiling point, and the filter was washed with 50 ml. of hot water. The filtrate was then cooled, and was extracted with three 100 ml. portions of ethyl acetate. The organic layers were combined, washed with 50 ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP82301482A 1981-03-27 1982-03-23 Process for preparing phenylalkanoic acids and derivatives of benzoxazole therefrom Ceased EP0062440A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24837981A 1981-03-27 1981-03-27
US248379 1981-03-27

Publications (1)

Publication Number Publication Date
EP0062440A1 true EP0062440A1 (en) 1982-10-13

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EP82301482A Ceased EP0062440A1 (en) 1981-03-27 1982-03-23 Process for preparing phenylalkanoic acids and derivatives of benzoxazole therefrom

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EP (1) EP0062440A1 (enrdf_load_stackoverflow)
JP (1) JPS57175142A (enrdf_load_stackoverflow)
CA (1) CA1176656A (enrdf_load_stackoverflow)
DK (1) DK139082A (enrdf_load_stackoverflow)
GB (1) GB2095670B (enrdf_load_stackoverflow)
GR (1) GR75153B (enrdf_load_stackoverflow)
IL (1) IL65320A0 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089805A3 (en) * 1982-03-24 1984-04-11 Eli Lilly And Company Process for preparing phenylalkanoic acids

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1435721A (en) * 1972-05-18 1976-05-12 Lilly Industries Ltd Benzoxazole derivatives
AT336570B (de) * 1974-03-09 1977-05-10 Hoechst Ag Verfahren zur herstellung von neuen sek. benzylaminen und deren saureadditionssalzen
US4087437A (en) * 1976-09-07 1978-05-02 Eli Lilly And Company 2-Phenyl-5-benzoxazolylalkanoic acid purification process
GB1522477A (en) * 1974-08-13 1978-08-23 Ici Ltd Process for the manufacture of rho-hydroxybenzyl cyanide
DE2931255A1 (de) * 1978-08-04 1980-02-28 Ravizza Spa Verfahren zur herstellung von benzoxazolylpropionsaeurederivaten

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1435721A (en) * 1972-05-18 1976-05-12 Lilly Industries Ltd Benzoxazole derivatives
AT336570B (de) * 1974-03-09 1977-05-10 Hoechst Ag Verfahren zur herstellung von neuen sek. benzylaminen und deren saureadditionssalzen
GB1522477A (en) * 1974-08-13 1978-08-23 Ici Ltd Process for the manufacture of rho-hydroxybenzyl cyanide
US4087437A (en) * 1976-09-07 1978-05-02 Eli Lilly And Company 2-Phenyl-5-benzoxazolylalkanoic acid purification process
DE2931255A1 (de) * 1978-08-04 1980-02-28 Ravizza Spa Verfahren zur herstellung von benzoxazolylpropionsaeurederivaten

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0089805A3 (en) * 1982-03-24 1984-04-11 Eli Lilly And Company Process for preparing phenylalkanoic acids

Also Published As

Publication number Publication date
IL65320A0 (en) 1982-05-31
CA1176656A (en) 1984-10-23
GB2095670A (en) 1982-10-06
GB2095670B (en) 1985-05-01
JPS57175142A (en) 1982-10-28
GR75153B (enrdf_load_stackoverflow) 1984-07-13
DK139082A (da) 1982-09-28

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Inventor name: GREENE, JAMES MICHAEL